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219 The functional activity of gavo-cel TRuC-T cells is not impaired by soluble mesothelin
  1. Michael Lofgren,
  2. Robert Tighe,
  3. Robert Hofmeister,
  4. Jian Ding,
  5. Nate Bagge,
  6. Alec Andrews,
  7. Michelle Fleury and
  8. Courtney Anderson
  1. TCR2 Therapeutics, Cambridge, MA, USA


Background Gavo-cel is an autologous and HLA-independent T-Cell Receptor Fusion Construct (TRuCTM) T cell therapy that targets mesothelin-expressing tumors and is under Phase 2 evaluation for treatment-resistant MPM, NSCLC, cholangiocarcinoma, and ovarian cancer tumors (NCT03907852). Mesothelin (MSLN) is a 71 kDa GPI-anchored membrane protein that undergoes proteolytic membrane shedding to generate soluble mesothelin-related peptides (sMRPs) whose levels are correlated with tumor burden in MPM. sMRPs contain the juxtamembrane epitope of that is recognized by the MH1 binder domain of the gavo-cel TRuC and whose levels are correlated with tumor burden in MPM. Because shed MLSN has been implicated as a potential obstacle to successful anti-MSLN therapies, including cell therapies, we assessed the impact of soluble MSLN (sMSLN) on the function of gavo-cel and or allogeneic anti-MSLN TRuC, MH1gd.

Methods In this study, we generated primary human TRuC-T cells modeling MSLN-targeting clinical agent gavo-cel or that express MH1gd TRuC, and then measured the impact of soluble MSLN on the in vitro activation, cytotoxicity, and cytokine response of gavo-cel or MH1gd during acute and chronic challenge with antigen-expressing tumor cells. We also evaluated whether sMRP in human serum impacts the in vitro cytotoxicity and cytokine response of gavo-cel in response to MSLN-expressing tumor cell lines.

Results High, supraphysiological levels of the full-length shed domain of MSLN, sMSLN, does not impair, block, or disrupt the effector function of gavo-cel or MH1gd TRuC-T cells with respect to in vitro cytotoxicity or cytokine production. Furthermore, gavo-cel demonstrates potent efficacy in vivo in a tumor model characterized by circulating sMSLN.

Conclusions Our data indicate that both gavo-cel and allogeneic MSLN-targeting TRuC-T cells are not susceptible to functional suppression by sMRPs, even at supraphysiological levels that far exceed those found in cancer patients.

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